Genome-Wide Identification of Rare and Common Variants Driving Triglyceride Levels in a Nevada Population

Abstract

Clinical conditions correlated with elevated triglyceride levels are well-known: coronary heart disease, hypertension, and diabetes. Underlying genetic and phenotypic mechanisms are not fully understood, partially due to lack of coordinated genotypic-phenotypic data. Here we use a subset of the Healthy Nevada Project, a population of 9,183 sequenced participants with longitudinal electronic health records to examine consequences of altered triglyceride levels. Specifically, Healthy Nevada Project participants sequenced by the Helix Exome+ platform were cross-referenced to their electronic medical records to identify: (1) rare and common single-variant genome-wide associations; (2) gene-based associations using a Sequence Kernel Association Test; (3) phenome-wide associations with triglyceride levels; and (4) pleiotropic variants linked to triglyceride levels. The study identified 549 significant single-variant associations (p < 8.75 × 10–9), many in chromosome 11’s triglyceride hotspot: ZPR1, BUD13, APOC3, APOA5. A well-known protective loss-of-function variant in APOC3 (R19X) was associated with a 51% decrease in triglyceride levels in the cohort. Sixteen gene-based triglyceride associations were identified; six of these genes surprisingly did not include a single variant with significant associations. Results at the variant and gene level were validated with the UK Biobank. The combination of a single-variant genome-wide association, a gene-based association method, and phenome wide-association studies identified rare and common variants, genes, and phenotypes associated with elevated triglyceride levels, some of which may have been overlooked with standard approaches.

The Impact of ACEs on BMI: An Investigation of the Genotype-Environment Effects of BMI

“…BMI measures for HNP participants were processed as published previously (Schlauch et al, 2020;Read et al, 2021). Briefly, multiple records were agglomerated while taking outlying measures into account.…”

“…Sequencing was performed at Helix (CLIA #05D2117342, CAP# 9382893) using a proprietary exome platform called Helix Exome+. This platform combines a medical-grade exome platform with hundreds of thousands additional genomic regions of interest, resembling a microarray backbone (Helix, 2019;Cirulli et al, 2020;Read et al, 2021). Full base pair level coverage histograms demonstrate that more than 90% of the bases have greater than or equal to 20x coverage for popular reference panels including ACMG-73.…”

“…This assay has also been validated with high reproducibility using high confidence calls from the Platinum genomes (Eberle et al, 2017) and the National Institute of Standards and Technology (NIST) Genome in a Bottle (GIAB) (Zook et al, 2014). All sequencing reads were aligned to GRCh38 and variant calls were made using Sentieon (Helix, 2019;Kendig et al, 2019) following established sequencing-specific quality control metrics and GATK best practices (Helix, 2019;Cirulli et al, 2020;Read et al, 2021).…”

“…Variants were annotated similar to previous HNP studies (Read et al, 2021), using dbSNP build 153 (ftp.ncbi.nlm.nih.gov/snp) and PhenoScanner V2 (Staley et al, 2016;Kamat et al, 2019). Additionally, the Ensembl Variant Effect Predictor v.101 and ClinVar were used for functional characterization.…”

“…The Healthy Nevada Project (HNP), is an all-comers population health study that was formed in 2016 (Read et al, 2019(Read et al, , 2021Cirulli et al, 2020;Grzymski et al, 2020;Schlauch et al, 2020). As of October 2021, the HNP includes 43,000 whole-exome sequenced participants who are cross-referenced with up to 16 years of Electronic Health Records (EHR).…”